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@ARTICLE{Shen:130557,
author = {Z. Shen and Y. Liu and B. Dewidar and J. Hu and O. Park and
T. Feng and C. Xu and C. Yu and Q. Li and C. Meyer and I.
Ilkavets and A. Müller and C. Stump-Guthier and S. Munker
and R. Liebe and V. Zimmer and F. Lammert and P. R. Mertens
and H. Li and P. Ten Dijke and H. Augustin$^*$ and J. Li and
B. Gao and M. P. Ebert and S. Dooley and Y. Li and H.-L.
Weng},
title = {{D}elta-{L}ike {L}igand 4 {M}odulates {L}iver {D}amage by
{D}own-{R}egulating {C}hemokine {E}xpression.},
journal = {The American journal of pathology},
volume = {186},
number = {7},
issn = {0002-9440},
address = {New York [u.a.]},
publisher = {Elsevier},
reportid = {DKFZ-2017-05636},
pages = {1874 - 1889},
year = {2016},
abstract = {Disrupting Notch signaling ameliorates experimental liver
fibrosis. However, the role of individual Notch ligands in
liver damage is unknown. We investigated the effects of
Delta-like ligand 4 (Dll4) in liver disease. DLL4 expression
was measured in 31 human liver tissues by
immunohistochemistry. Dll4 function was examined in carbon
tetrachloride- and bile duct ligation-challenged mouse
models in vivo and evaluated in hepatic stellate cells,
hepatocytes, and Kupffer cells in vitro. DLL4 was expressed
in patients' Kupffer and liver sinusoidal endothelial cells.
Recombinant Dll4 protein (rDll4) ameliorated hepatocyte
apoptosis, inflammation, and fibrosis in mice after carbon
tetrachloride challenge. In vitro, rDll4 significantly
decreased lipopolysaccharide-dependent chemokine expression
in both Kupffer and hepatic stellate cells. In bile duct
ligation mice, rDll4 induced massive hepatic necrosis,
resulting in the death of all animals within 1 week.
Inflammatory cell infiltration and chemokine ligand 2 (Ccl2)
expression were significantly reduced in rDll4-receiving
bile duct ligation mice. Recombinant Ccl2 rescued bile duct
ligation mice from rDll4-mediated death. In patients with
acute-on-chronic liver failure, DLL4 expression was
inversely associated with CCL2 abundance. Mechanistically,
Dll4 regulated Ccl2 expression via NF-κB. Taken together,
Dll4 modulates liver inflammatory response by
down-regulating chemokine expression. rDll4 application
results in opposing outcomes in two models of liver damage.
Loss of DLL4 may be associated with CCL2-mediated cytokine
storm in patients with acute-on-chronic liver failure.},
keywords = {Chemokine CCL2 (NLM Chemicals) / Chemokines (NLM Chemicals)
/ Intracellular Signaling Peptides and Proteins (NLM
Chemicals) / Membrane Proteins (NLM Chemicals) / delta
protein (NLM Chemicals)},
cin = {A190 / L101},
ddc = {610},
cid = {I:(DE-He78)A190-20160331 / I:(DE-He78)L101-20160331},
pnm = {311 - Signalling pathways, cell and tumor biology
(POF3-311)},
pid = {G:(DE-HGF)POF3-311},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:27171900},
pmc = {pmc:PMC4929401},
doi = {10.1016/j.ajpath.2016.03.010},
url = {https://inrepo02.dkfz.de/record/130557},
}